The genetic control of pattern formation during embryogenesis and the genetic basis for sporadic congenital anomalies are two important problems in mammalian developmental genetics. An unusual mouse mutation called disorganization (Ds) provides an exceptional model for studying both problems. Ds disrupts the orderly processes of development and causes an exceptional variety of birth defects involving all three germ layers and most body parts. These defects include aplasia, malformation, or ectopic development of many body structures. Many of these appear to result from problems in establishing symmetry, perhaps by causing mirror-image duplications. Highly variable expression and very low penetrance found in mice with the Ds mutation are characteristic of many sporadic congenital anomalies in humans. The long-term goal is to use Ds as a model for studying pattern formation and factors that contribute to many sporadic birth defects. Three specific aims will be used to accomplish these goals: Specific Aim I Complete the genetic and physical map of the Ds locus. These maps are the foundation for identifying candidate genes. Specific Aim 2 Identify and characterize candidate genes by finding and genetically mapping transcribed sequences and by characterizing their expression patterns. Specific Aim 3 Test whether Ds affects pattern formation by causing symmetrical anomalies (e.g. mirror-image or parallel duplications). Mouse mutants that cause syndactylies or polydactylies will be used to mark specific digits. The occurrence and location of these digit anomalies will be examined in mice that are heterozygous (or homozygous) both for Ds and for each of these other mutations. We will also test whether Ds and these other loci are in the same developmental pathway by determining whether novel congenital anomalies occur in double heterozygotes (or homozygotes).